Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/12—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/42—Oxygen atoms attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
  • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• This invention relates to novel ester derivatives, processes for preparing them, pharmaceutics containing them and their use as medicines, especially for the treatment of various diseases of the respiratory system.
• Antagonism to muscarinic receptors are known to cause bronchodilation, gastrointestinal hypanakinesis, gastric hyposecretion, dry mouth, mydriasis, suppression of bladder contraction, hypohydrosis, tachycardia and the like [cf. "Basic and Clinical Pharmacology , 4th ed., (APPLETON & LANGE), pp.83 - 92, (1989); and Drug News & Perspective, 5(6), pp.345 - 352 (1992)].
• M 1 receptors are present mainly on the brain; M 2 receptors, on the heart; and M 3 receptors, on the smooth muscles and glandular tissues.
• M 3 receptors on the smooth muscles and glandular tissues.
• the object of the present invention is to provide treating agents of diseases associated with muscarine M 3 receptors, which exhibit highly selective antagonism to muscarine M 3 receptors but little side effect and hence are safe and effective.
• A signifies a group expressed by a formula (a 0 ) or (b 0 );
• Ar signifies aryl or heteroaryl optionally having substituent(s) selected from a group consisting of halogen, lower alkyl, lower alkenyl and lower alkoxy;
• B 1 and B 2 signify, independently of each other, straight chain, branched chain and/or cyclic portion-containing C 2 - C 10 saturated or unsaturated aliphatic hydrocarbon which may have hyroxyl group(s) and/or be interrupted with nitrogen atom(s);
• R 1 signifies a fluorine-substituted C 4 - C 6 cycloalkyl optionally having hydroxyl group(s);
• R 2 , R 3 and R 4 signify, either independently of each other, a lower alkyl optionally having substituent(s) selected from a group consisting of phenyl and cycloalkyl, or R 2 and R 3
• the compounds very useful for treating various diseases associated with muscarine M 3 receptors e.g., respiratory diseases such as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, chronic respiratory tract obstruction, fibroid lung, pulmonary emphysema and rhinitis.
• respiratory diseases such as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, chronic respiratory tract obstruction, fibroid lung, pulmonary emphysema and rhinitis.
• the present invention is whereupon completed.
• This invention relates to the compounds represented by the general formula (I) or salts thereof, and their production processes and their utility.
• the invention furthermore relates to the compounds which are intermediate products of the compounds represented by the general formula (I) and exhibit highly selective antagonism to muscarine M 3 receptors, i.e., the compounds represented by a general formula (II) [in which A p signifies a group represented by a formula (a p0 ) or (b p0 ) R 20 signifies hydrogen or a lower alkyl optionally having substituent(s) selected from a group consisting of phenyl and cycloalkyl; R 40 signifies lower alkyl which may have substituent(s) selected from a group consisting of phenyl and cycloalkyl, or a single bond or a C 1 - C 3 alkylene group binding to a bindable optional site on B 1 ; and Ar, B 1 , B 2 , R 1 and R 5 have the earlier given significations] and salts thereof.
• a p signifies a group represented by a formula (a p0 ) or (b
• Halogen means fluorine, chlorine, bromine and iodine atoms.
• “Lower alkyl” means C 1 - C 6 straight chain or branched alkyl groups, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups.
• “Lower alkenyl” means C 2 - C 6 straight chain or branched alkenyl groups, examples of which include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl and 4-pentenyl groups.
• “Lower alkoxy” means C 1 - C 6 straight chain or branched alkoxy groups or C 1 - C 3 alkylenedioxy groups, examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, methylenedioxy, ethylenedioxy and trimethylenedioxy groups.
• Aryl means C 6 - C 11 aryl groups, examples of which include phenyl and naphthyl groups.
• Heteroaryl means 5- or 6- membered monocyclic heteroaryl groups containing one or two same or different hetero atoms selected from a group consisting of nitrogen, oxygen and sulfur atoms, or condensed ring-type heteroaryl groups formed by condensation of one of said monocyclic heteroaryl groups with one of aforesaid aryl groups, or by mutual condensation of same or different monocyclic heteroaryl groups as above-explained, examples of which include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 2-thienyl, 3-thienyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-
• "Straight chain, branched chain and/or cyclic portion-containing C 2 - C 10 saturated or unsaturated aliphatic hydrocarbon which may have hydroxyl group(s) and/or be interrupted with nitrogen atom(s)” means straight chain, branched chain and/or cyclic portion-containing C 2 - C 10 saturated or unsaturated aliphatic hydrocarbon groups which have 1, 2 or more, preferably 1, hydroxyl group(s) on optional, substitutable position(s) on such saturated or unsaturated aliphatic hydrocarbon group or do not have them and, furthermore, which are interrupted with 1, 2 or more, preferably 1, nitrogen atom(s) at interruptable, optional position(s) in the hydrocarbon chain of said group or not interrupted, examples of which include those groups represented by formulae (11) or those of the above formulae which however have 1, 2 or more, preferably 1, hydroxyl group(s) at optional, substitutable position(s) thereof.
• Cycloalkyl means C 3 - C 7 cycloalkyl groups, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
• C 2 - C 5 alkylene which may be interrupted with oxygen means C 2 - C 5 alkylene groups which are interrupted with 1, 2 or more, preferably 1, oxygen atom(s) at interruptable, optional site(s) in said alkylene chain or not interrupted, examples of which include ethylene, trimethylene, tetramethylene, pentamethylene, 2-oxatetramethylene, 2-oxapentamethylene and 3-oxapentamethylene groups.
• C 1 - C 3 alkylene examples include methylene, ethylene and trimethylene groups.
• C 1 - C 6 saturated or unsaturated aliphatic hydrocarbon which may be mutually crosslinked means C 1 - C 6 saturated or unsaturated aliphatic hydrocarbon groups which are not mutually crosslinked or have a mutual single bond or C 1 - C 4 crosslinkage.
• Examples of said C 1 - C 6 saturated or unsaturated aliphatic hydrocarbon groups are divalent or trivalent groups formed of, e.g., methane, ethane, propane, propene, butane, 1-pentene, hexane or the like.
• monocyclic groups comprising, e.g., aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, tetrahydropyridine ring or 2-vinylpiperidine ring; whereas, when they have crosslinkage, bicyclic groups comprising, e.g., 8-azabicyclo [3.2.1] octane ring, 3-azabicyclo [3.3.0] octane ring or 3-azabicyclo [3.3.1] nonane ring.
• [Anion] is to make a pair with the ammonium ion on a compound of the present invention to electrically neutralize said compound and is not subject to any particular limitation so long as it is pharmaceutically acceptable.
• Salts of the compounds represented by the general formula (I) means, for example, customary pharmaceutically acceptable salts of the compounds in which "A" in the formula stands for the groups expressed by formula (b 0 ).
• inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
• organic carboxylic acid salts such as benzoate, maleate, fumarate, succinate, tartarate, citrate and ascorbate
• organic sulfonic acid salts such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate may be named.
• Treating agent means medicines which are applied to patients suffering from various diseases for therapeutic and/or prophylactic purposes.
• Inhalant means those medicines per se well known in the medical field, which are in the form of being used by inhaling through the respiratory organ at the application time, such as aerosol, inhalant powder, inhalant liquid, and the like.
• the compounds of the present invention in occasions have stereoisomers or tautomers such as optical isomers, diastereoisomers or geometrical isomers, depending on configuration of substituents.
• stereoisomers or tautomers such as optical isomers, diastereoisomers or geometrical isomers, depending on configuration of substituents.
• the invention includes all of such stereoisomers, tautomers and their mixtures within its scope.
• A signifies the groups expressed by the formulae (a 0 ) or (b 0 )
• B 1 and B 2 signify, independently of each other, straight chain, branched chain and/or cyclic portion-containing C 2 - C 10 saturated or unsaturated aliphatic hydrocarbon which may have hydroxyl 5 group(s) and/or be interrupted with nitrogen atom(s).
• R 2 , R 3 and R 4 signify, either independently of each other, a lower alkyl optionally having substituent(s) selected from a group consisting of phenyl and cycloalkyl, or R 2 and R 3 together signify a C 2 - C 5 alkylene which may be interrupted with oxygen, or R 4 signifies a single bond or C 1 - C 3 alkylene binding to a bindable optional site on B 1 , and X - signifies an anion.
• cycloalkyl which can be present as the substituent, for example, cyclohexyl, cycloheptyl and the like are preferred.
• R 2 , R 3 or R 4 are "lower alkyl", for example, methyl, ethyl, propyl, isopropyl and the like are preferred.
• R 2 , R 3 and R 4 represent, independently of each other, "lower alkyl optionally having substituent(s)", specific examples include methyl, ethyl, propyl, isopropyl, cyclohexylmethyl, cycloheptylmethyl, benzyl and the like, methyl being preferred.
• C 2 - C 5 alkylene which may be interrupted with oxygen formed by R 2 and R 3 together, for example, tetramethylene, pentamethylene, 3-oxapentamethylene and the like are convenient. In particular, 3-oxapentamethylene group is preferred.
• R 4 binds to a bindable optional site on B 1 , single bond or methylene or ethylene are preferred as such R 4 .
• R 2 , R 3 and R 4 for example, R 2 and R 3 either stand for, independently of each other, lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl; or R 2 and R 3 together signify a C 2 - C 5 alkylene which may be interrupted with oxygen and R 4 signifies a single bond or C 1 - C 3 alkylene which binds to a bindable optional site on B 1 .
• X - for example, anions formed from halogen atoms such as Cl - , Br - , and the like are preferred.
• preferred embodiments of A in the general formula (I) in which A is a group represented by the formula (a 0 ) include, for example, a group expressed by a formula (a 1 ) [in which B 11 and B 12 are, independently of each other, C 1 -C 6 saturated or unsaturated aliphatic hydrocarbon groups, which may be mutually crosslinked; k is 0, 1 or 2; and R 2 , R 3 and X - have the earlier given significations (provided that the sum of carbon atoms of B 11 and B 12 , carbon atoms forming the crosslinkage and k does not exceed 13)].
• a formula (a 1 ) in which B 11 and B 12 are, independently of each other, C 1 -C 6 saturated or unsaturated aliphatic hydrocarbon groups, which may be mutually crosslinked; k is 0, 1 or 2; and R 2 , R 3 and X - have the earlier given significations (provided that the sum of carbon atoms of B 11 and B 12 , carbon atom
• A a group expressed by any one of formulae (a 2 ): [in which R 21 and R 31 signify lower alkyl independently of each other; and k and X - have the earlier given significations] is preferred.
• A is a group expressed by a formula (as) [in which k, R 21 , R 31 and X - have the earlier given significations] or a formula (a 4 ) [in which k, R 21 , R 31 and X - have the earlier given significations].
• R 5 signifies hydrogen or a lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl
• R 7 signifies hydrogen or a lower alkyl; or either one of R 5 and R 7 signifies a single bond or C 1 - C 3 alkylene binding to a bindable optional site on B 2 .
• R 5 "lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl", signifies the same to the earlier given definition of R 2 , R 3 or R 4 , "lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl", specific examples of which also being the same. Of those named examples, methyl and ethyl are preferred.
• R 5 and R 7 binds to a bindable optional site on B 2
• preferred R 5 or R 7 is single bond, methylene or ethylene.
• R 6 signifies hydrogen, lower alkyl or a group represented by -N(R 8 )R 9 .
• R 6 As lower alkyl represented by R 6 , methyl, ethyl, propyl and butyl are preferred.
• R 8 and R 9 signify, independently of each other, hydrogen or lower alkyl.
• R 8 or R 9 As lower alkyl represented by R 8 or R 9 , methyl, ethyl, and propyl are preferred.
• both R 8 and R 9 are hydrogen atoms.
• groups expressed as -N(R 8 )R 9 for example, amino, methylamino, dimethylamino, ethylmethylamino and diethylamino, in particular, amino, are preferred.
• R 6 hydrogen and those groups expressed as -N(R 8 )R 9 are preferred, hydrogen being the most preferred.
• R 5 signifies a single bond or a C 1 - C 3 alkylene binding to a bindable optional site on B 2 ;
• R 6 signifies hydrogen, lower alkyl or a group expressed as -N(R 8 )R 9 , preferably hydrogen; and
• R 7 signifies hydrogen.
• a in the general formula (I) is a group expressed by the formula (b 0 )
• A is a group represented by a formula (b 1 ) [in which B 21 and B 22 signify, independently of each other, a C 1 - C 6 saturated or unsaturated aliphatic hydrocarbon group, which may be mutually crosslinked; m signifies 0, 1 or 2; R 71 signifies hydrogen or lower alkyl; and R 6 has the earlier given signification (provided that the sum of carbon atoms of B 21 and B 22 , carbon atoms forming the crosslinkage and m does not exceed 13)], in particular, R 71 in that group is hydrogen.
• A is a group represented by any one of the formulae (b 2 ) [in which m and R 6 have the earlier given significations]. It is of particular advantage that A is a group represented by a formula (b 3 ) [in which m and R 6 have the earlier given significations],
• m is preferably 1 or 2.
• R 6 is preferably hydrogen.
• Ar signifies aryl or heteroaryl optionally having substituent(s) selected from a group consisting of halogen, lower alkyl, lower alkenyl and lower alkoxy.
• Aryl or heteroaryl optionally having substituent(s) selected from a group consisting of halogen, lower alkyl, lower alkenyl and lower alkoxy signify unsubstituted aryl or heteroaryl, or the aryl or heteroaryl having substituent(s) at substitutable optional position(s) thereon, said 1, 2 or more, preferably 1 or 2, substituent(s) which are the same or different and selected from the group consisting of halogen, lower alkyl, lower alkenyl and lower alkoxy.
• substituent halogen for example, fluorine, chlorine and bromine are preferred.
• substituent lower alkyl for example, methyl, ethyl, propyl and isopropyl are preferred.
• substituent lower alkenyl for example, vinyl is preferred.
• substituent lower alkoxy for example, methoxy, ethoxy and methylenedioxy are preferred.
• Ar is "aryl", for example, phenyl is preferred.
• Ar is "heteroaryl", for example, 2-pyridyl, 2-thiazolyl, 2-thienyl and 3-thienyl are preferred.
• phenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-vinylphenyl and 3,4-methylenedioxyphenyl are preferred.
• a in the general formula (I) is a group represented by the formula (a 0 )
• 4-chlorophenyl is preferred
• A is a group represented by the formula (b 0 )
• unsubstituted phenyl is preferred.
• R 1 signifies a fluorine-substituted C 4 - C 6 cycloalkyl optionally having hydroxyl group(s).
• “Fluorine-substituted C 4 - C 6 cycloalkyl optionally having hydroxyl group(s)” include C 4 - C 6 cycloalkyl substituted with 1, 2 or more, preferably 1 or 2, inter alia, 2 fluorine atoms at substitutable, optional position(s), said cycloalkyl groups further having 1, 2 or more, preferably 1, hydroxyl group(s) at substitutable optional position(s) thereon or not having them.
• cycloalkyl of R 1 for example, cyclopentyl is preferred.
• examples of R 1 include 1-fluorocyclobutyl, 1-fluorocyclopentyl, 2-fluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclobutyl, 3-fluorocyclopentyl, 2,2-difluorocyclobutyl, 2,2-difluorocyclopentyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclopentyl, 3,3-difluoro-4-hydroxycyclopentyl, 3,3,4,4-tetrafluorocyclopentyl, 2,3-difluorocyclobutyl, 2,3-difluorocyclopentyl, 3,4-difluorocyclopentyl, 2,2,3,3-tetrafluorocyclobutyl and 2,2,3,3-tetrafluorocyclopentyl.
• 2-fluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclobutyl, 3-fluorocyclopentyl, 2,2-difluorocyclobutyl, 2,2-difluorocyclopentyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclopentyl, 3,3-difluoro-4-hydroxycyclopentyl, 3,3,4,4-tetrafluorocyclopentyl and 2,2,3,3-tetrafluorocyclopentyl are convenient.
• 3,3-difluorocyclopentyl is preferred.
• a p signifies a group represented by the formulae (a p0 ) or (b p0 ) [in which B 1 , B 2 , R 5 , R 20 and R 40 have the earlier given significations].
• preferred embodiments of the compounds represented by the general formula (II) correspond to the preferred embodiments of the compounds represented by the general formula (I).
• R 20 or R 40 independently of each other, methyl, ethyl, propyl, isopropyl, cyclohexylmethyl, cycloheptylmethyl and benzyl can be named, in particular, methyl being preferred.
• R 40 a single bond or C 1 - C 3 alkylene which bind to a bindable optional site on B 1 , in particular, a single bond, methylene or ethylene are preferred.
• a p is a group represented by the formula (a p0 ), for example, A p is a group represented by a formula (a p1 ) [in which B 11 , B 12 , k and R 20 have the earlier given significations], in particular, a group represented by any one of formulae (a p2 ) [in which k and R 20 have the earlier given significations].
• a p is a group represented by a formula (a p3 ) [in which k and R 20 have the earlier given significations] or a formula (a p4 ) [in which k and R 20 have the earlier given significations].
• a p is a group represented by the formula (b p0 ), for example, A p is a group represented by a formula (b p1 ) [in which B 21 , B 22 and m have the earlier given significations], in particular, is a group represented by any one of formulae (b p2 ) [in which m has the earlier given signification]. In most favorable embodiments, A p is a group represented by a formula (b p3 ) [in which m has the earlier given signification].
• examples similar to those named for Ar or R 1 of the general formula (I) can be named, preferred examples again being the same.
• Specific examples of B 11 , B 12 , B 21 , B 22 , k, m or R 5 in the formulae (a p1 ), (a p2 ), (a p3 ), (a p4 ), (b p0 ), (b p1 ), (b p2 ) or (b p3 ) are same to those for B 11 , B 12 , B 21 , B 22 , k, m or R 5 in the formulae (a 1 ), (a 2 ), (a 3 ), (a 4 ), (b 0 ), (b 1 ), (b 2 ) or (b 3 ), preferred examples again being the same.
• salts of the compounds represented by the general formula (II), for example, those acid addition salts via basic nitrogen atoms can be named.
• inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
• organic acid salts such as maleate, fumarate, tartarate, citrate, asocorbate and trifluoroacetate
• sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate
• Compounds (I) of the present invention can be produced, for example, by the following processes or those described in working examples, it being understood that production processes of the compounds (I) of the present invention are not limited by these reaction examples.
• Salts of the compounds represented by the general formula (II-1) signify acid addition salts via amino or imino, examples of which include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; organic acid salts such as maleate, fumarate, tartarate, citrate, ascorbate and trifluoroacetate; and sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
• inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate
• organic acid salts such as maleate, fumarate, tartarate, citrate, ascorbate and trifluoroacetate
• sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate and p-
• L for example, halogen atoms such as chlorine, bromine and iodine; alkylsulfonyloxy group such as methylsulfonyloxy: and arylsulfonyloxy group such as p-toluenesulfonyloxy may be named.
• reaction of a compound represented by the general formula (II-1) or a salt thereof with a compound represented by the general formula (III) is normally conducted in an inert solvent having no adverse influence on the reaction.
• inert solvent for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; halogenated solvents such as chloroform and dichloromethane; aprotic polar solvents such as acetone and acetonitrile; or mixed solvents of the foregoing can be used.
• ethers such as diethyl ether, tetrahydrofuran and dioxane
• aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene
• halogenated solvents such as chloroform and dichloromethane
• aprotic polar solvents such as acetone and acetonitrile
• mixed solvents of the foregoing can be used.
• the compound of the general formula (III) is normally used at the ratios of 1 mol - molar excess, in particular, 1 - 10 mols, per mol of the (II-1) compound. Especially when R 20 in the (II-1) compound is hydrogen, at least 2 mols of (III) compound is used.
• the reaction temperature is normally in a range from about 0°C to boiling point of the solvent, and the reaction time, from 10 minutes to 48 hours, while those conditions deviating from above ranges can be used where necessary.
• the above reaction may be conducted in the presence of a base, for smooth progress of the reaction.
• alkali metal bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate
• alkali metal carbonates such as sodium carbonate and potassium carbonate
• tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline may be named.
• the use rate of said base is normally in a range of 1 mol-molar excess, preferably 1 - 10 mols, per mol of the (II-1) compound.
• salts of the compounds represented by the genral formula (II-2) those similar to the salts of the compounds (II-1) in the above production process 1 can be named.
• L 1 or L 2 "leaving group” same leaving groups as those expressed as L in the above production process 1 can be named.
• reaction of a compound of the general formula (II-2) or a salt thereof with a compound of the general formyla (IV) can be conducted in the manner similar to the reaction of a compound of the general formula (II-1) or a salt thereof with a compound of the general formula (III) in the production process 1.
• a compound of a general formula (I-3) [in which R 70 signifies hydrogen or a lower alkyl, and Ar, B 2 , R 1 , R 5 and R 6 have the earlier given significations] or a salt thereof can be produced.
• salts of the compounds represented by the general formula (II-3), (V) or (VI) those similar to the named salts of compounds (II-1) in the production process 1 can be used.
• halogen such as chlorine, bromine and iodine
• lower alkoxy such as methoxy, ethoxy, butoxy, propoxy and isopropoxy
• lower alkylthio such as methylthio and ethylthio
• 1-imidazolyl, 1-pyrazolyl, 1-benzotriazolyl and the like may be named.
• aralkyl such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and trityl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl and pivaloyl; benzoyl; arylalkanoyl such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and tert-butoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl; lower alkylsilyl such as trimethylsilyl and tert-butyldimethyl
• nitro can be named.
• those protective groups in particular, acetyl, pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl groups are preferred.
• reaction of a compound of the general formula (II-3) or a salt thereof with a compound of the general formula (V) or a salt thereof is normally conducted in an inert solvent having no adverse effect on the reaction, using 1 mol - molar excess, preferably 1 - 2 mols, of the compound (V) or a salt thereof, per mol of the compound (II-3) or a salt thereof.
• the inert solvent for example, alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; aprotic polar solvents such as dimethylsulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide or their mixtures can be used.
• alcohols such as methanol and ethanol
• ethers such as diethyl ether, tetrahydrofuran and dioxane
• aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene
• aprotic polar solvents such as dimethylsulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide or their mixtures can be used.
• the reaction temperature is normally in a range from -70°C to boiling point of the solvent used in the reaction, preferably from -20°C to 100°C.
• the reaction time normally ranges from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
• the reaction may be conducted in the presence of a base, for smooth progress of the reaction.
• the use rate of said base is normally in a range of 1 mol-molar excess, preferably 1 - 10 mols, per mol of the compound (V) where said compound contains a protective group.
• an unprotected compound is used as the compound (V)
• a salt of the same compound is used.
• an equivalent amount to the product of an acid be present in the reaction system and as the acid, one derived from the salt of the compound (V) can be utilized.
• the reaction is preferably conducted in the presence of a base of an amount suitable for neutralizing the excessive acid in the present reaction system.
• Method for removing protective groups differs depending on such factors as the kind of the protective groups and stability of the object compound (I-3).
• the deprotection can be carried out using the methods known per se , for example, those described in Protective Groups in Organic Synthesis , T. W. Greene, John Wiley & Sons Co., Ltd.
• solvolysis using an acid or a base that is, a method in which 0.01 mole to over excess of an acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid and the like, or equimole to over excess of a base, preferably potassium hydroxide, calcium hydroxide and the like are acted; chemical reduction using a metal hydride complex; or catalytic reduction using a palladium-carbon catalyst, a Raney nickel catalyst or the like.
• a pb1 signifies a group represented by a formula (b p01 )
• B 23 signifies a straight chain, branched chain and/or cyclic portion-containing C 2 - C 10 saturated or unsaturated aliphatic hydrocarbon which may have hydroxyl group(s) and/or be interrupted with nitrogen atom(s);
• R 71 signifies a single bond or a C 1 - C 3 alkylene;
• Ar and R 1 have the earlier given significations] or a salt thereof, and subsequent optional introduction into the same compound a lower alkyl
• a compound represented by a general formula (I-4) [in which Ar, B 23 , R 1 , R 5 , R 6 and R 71 have the earlier given significations] or a salt thereof can be prepared.
• salts of the compounds of the general formula (VII) those similar to the salts of the compounds (II-1) used in the production process 1 can be named as examples.
• the lower alkyl-introducing reaction can be optionally conducted, by methods known per se or those analogous thereto, by using, for example, alkyl iodide, dialkyl sulfate, and the like.
• Isolation and purification of those compounds represented by the general formulae (I-1), (I-2), (I-3) or (I-4) or their salts can be conducted by applying customary separation means such as column chromatography using silica gel, adsorbent resin or the like; liquid chromatography; solvent extraction, or recrystallization, reprecipitation and the like, either singly or in suitable combination.
• customary separation means such as column chromatography using silica gel, adsorbent resin or the like; liquid chromatography; solvent extraction, or recrystallization, reprecipitation and the like, either singly or in suitable combination.
• anion-converting methods for example, a method comprising adsorbing a compound of the general formula (I-1) or (I-2), which has a certain kind of anion, onto a column filled with a suitable carrier, treating the same with a salt of an acid capable of providing an excess of a desired anion, and thereafter eluting the formed compound having the desired kind of anion can be used.
• Compounds represented by the general formula (I-3) or (I-4) or their salts can be converted from free compounds to pharmaceutically acceptable salts by conventional methods.
• the salts can also be converted to free compounds.
• Compounds represented by the general formula (I-3) or (I-4) are preferably isolated in the form of their salts, and therefore, after being isolated as a certain kind of salt, can be converted into a different, desired kind of salt.
• salt-converting methods for example, a method comprising adsorbing a salt of a compound of the general formula (I-3) or (I-4) onto a column filled with a suitable carrier, treating the same with an excess of a salt of a desired acid and thereafter eluting the formed, desired salt of the same compound can be used.
• a pp signifies a group represented by the formula (a p0 ) or (b p0p )
• R p signifies a protective group of amino or imino, or hydrogen, or a lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl
• a p , Ar, B 1 , B 2 , R 1 , R 6 , R 20 and R 40 have the earlier given significations.
• This production method is for making compounds of the general formula (II).
• a compound of the general formula (II) can be prepared by causing a compound of the general formula 2 to act on a carboxylic acid of the general formula 1 or a reactive derivative thereof to form a compound of the general formula 3 , and optionally removing the protective group in said compound 3 .
• the reaction between carboxylic acid of the general formula 1 or a reactive derivative thereof with a compound of the general formula 2 is normally conducted using 1 - 5 moles, preferably 1 - 2 moles, of the compound 2 per mole of the compound 1 or a reactive derivative thereof.
• reactive derivatives of the carboxylic acid represented by the general formula 1 for example, mixed acid anhydrides, active esters and active amides can be named, which can be obtained, for example, by those methods described in Internationl Publication WO 98/05641.
• the reaction is preferably carried out in the presence of a condensing agent such as carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, diphenylphosphorylazide, dipyridyldisulfide-triphenylphosphine and the like, in particular, carbonyldiimidazole.
• a condensing agent such as carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, diphenylphosphorylazide, dipyridyldisulfide-triphenylphosphine and the like, in particular, carbonyldiimidazole.
• the use rate of the condensing agent is not subject to strict limitation, while it is normally used in a range of 1 - 5 moles, preferably 1 - 2 moles, per mole of the carboxylic acid of the general formula 1 .
• the reaction is normally carried out in an inert solvent.
• inert solvent diethyl ether, tetrahydrofuran, N,N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane and trichloroethylene, or their mixtures can be named.
• diethyl ether, tetrahydrofuran, N,N-dimethylformamide and dioxane are preferred.
• the reaction temperature normally ranges from -70°C to boiling point of the used solvent, preferably from -20°C to 100°C.
• the reaction time normally ranges from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
• the reaction can also be conducted in the presence of a base, for smooth progress of the reaction.
• sodium hydride for example, sodium hydride; alkali metal bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclol5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline may be named. Of these, sodium hydride is preferred.
• the use rate of the base can range from the catalytic amount to 5 moles, preferably the catalytic amount, per mole of the carboxylic acid of the general formula 1 or its reactive derivative.
• amino- or imino-protective groups those protective groups described in above production process 3 can be used.
• Compounds represented by the general formula (II) can also be prepared by the steps of producing, in the manner similar to the above production process, a compound of the general formula (II) in which R 5 , R 20 or R 40 in the group A p is(are) hydrogen, and introducing into said compound a lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl.
• the reaction for introducing said lower alkyl can be conducted by subjecting the compound of the general formula (II) in which R 5 , R 20 or R 40 in the group A p is(are) hydrogen and (a) an aldehyde or ketone expressed as a general formula 5, [in which R 44 signifies a lower alkylidene optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl] to reducing amination reaction, or (b) after removing the protective group(s) of said amino or imino group(s), reacting said compound with a compound expressed as a general formula 6, [in which L 4 signifies a leaving group, and R 45 signifies a lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl] in the presence of a base, to provide a compound within the scope of the general formula (II), in which R 20 , R 40 or R 5 are, independently of each other, lower alkyl
• R 44 which is "a lower alkylidene optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl" signifies the one which can be converted to the corresponding "lower alkyl optionally having substituent(s) selected from the group consisting of phenyl and cycloalkyl" after termination of the above reaction.
• halogen such as chlorine, bromine and iodine
• alkylsulfonyloxy such as methylsulfonyloxy
• arysulfonyloxy such as p-toluenesulfonyloxy
• the reducing amination reaction with the ketone or aldehyde in above step (a) is normally conducted in an inert solvent not detrimental to the reaction.
• useful inert solvent examples include alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; and solvent mixtures thereof.
• alcohols such as methanol and ethanol
• ethers such as diethyl ether, tetrahydrofuran and dioxane
• aromatic hydrocarbons such as benzene and toluene
• solvent mixtures thereof solvent mixtures thereof.
• methanol, ethanol, tetrahydrofuran and toluene are preferred.
• the reaction temperature can normally be in the range of from about -30°C to about 200°C, preferably from about 0°C to about 100°C.
• the reaction time can normally be in the range of from 10 minutes to 7 days, preferably from 10 minutes to 24 hours.
• the above reducing amination reaction can be conducted by using a reducing agent such as a metal hydride complex, e.g., sodium borohybride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride or a mixture of sodium cyanoborohydride with zinc chloride; or by catalytic reduction using a palladium-on-carbon catalyst, a Raney nickel catalyst or the like.
• a metal hydride complex e.g., sodium borohybride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride or a mixture of sodium cyanoborohydride with zinc chloride
• a metal hydride complex e.g., sodium borohybride, sodium cyanoborohydride, lithium aluminum hydride, sodium triacetoxyborohydride or a mixture of sodium cyanoborohydride with zinc chloride
• the use rate of the reducing agent is normally in a range of 1 mole-molar excess, preferably 1 - 10 moles, per mole of the starting compound.
• the reaction with a compound which is expressed as the general formula 6 in the step (b) is normally conducted in the presence of a base, in an inert solvent not detrimental to the reaction.
• alkali metal bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate
• alkali metal carbonates such as sodium carbonate and potassium carbonate
• tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline may be named.
• N,N-diisopropylethylamine and potassium carbonate are preferred.
• the use rate of the base can normally range 1 mole - molar excess, preferably 1 - 10 moles, per mole of the starting compound.
• ethers such as diethyl ether, tetrahydrofuran and dioxane
• aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene
• aprotic polar solvents such as dimethylsulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric acid triamide; or their mixtures can be named.
• the reaction temperature can normally range from about 0°C to boiling point of the solvent used, and the reaction time can range from 10 minutes to 48 hours. Where necessary, however, more or less of these ranges can be used.
• This production process is that for producing the compounds represented by the general formula (VII).
• a compound represented by the general formula (VII) can be prepared by having a compound represented by the general formula 4 act on a carboxylic acid represented by the general formula 1 or a reactive derivative thereof.
• the reaction between a carboxylic acid of general formula 1 or a reactive derivative thereof with a compound of the general formula 4 can be carried out in the manner similar to the reaction between a carboxylic acid of general formula 1 or a reactive derivative thereof with a compound of the general formula 2 in above production process A.
• the filter was dried at 50°C for an hour, then a scintillator (Packard, Microscinti 0) was added, and the radioactivity of [ 3 H]-N-methylscopolamine adsorbed onto the filter was counted with a microplate scintillation counter (Packard, TopCount). Receptor non-specific binding of [ 3 H]-N-methylscopolamine was determined by adding 1 ⁇ M N-methylscopolamine.
• a scintillator Packard, Microscinti 0
• the binding affinity of each compound of the present invention to muscarinic receptors is expressed as dissociation constant (Ki) calculated from the concentration of tested compound which achieves 50% inhibition (IC 50 value) of binding of labeled ligand, [ 3 H]-N-methylscopolamine, following the method of Cheng and Prusoff [ Biochem Pharmacol., Vol. 22, pp. 3099-3108 (1973)] Inhibition Action on Binding to Muscarinic m 2 and m 3 Receptors Ki(nM) m 2/ m 3 m 2 m 3 Compound of Example 6 29.1 0.425 68.5 Compound of Example 54 4.76 0.079 60.2
• K B value The antagonistic potency of the test compound was determined from the degree of shift of the dose-response curve obtained by treatment with individual test compound of the present invention.
• the preparation After being equilibrated for an hour, the preparation was made to contract twice by treatment with 10 -4 M carbachol, and the second contraction induced by carbachol was used as the reference contraction. After the preparation was washed with fresh solution to be restored to the base line, a vehicle or one of the test compounds was administered to another preparation prepared from the same individual. Twenty minutes later, carbachol (1.7 nM - 36 mM) was cumulatively administered in three-fold increasing doses to obtain a dose-response curve. The dose-response curve was plotted by expressing responses as percentages based on the reference contraction of the preparation as 100%.
• K B value The antagonistic potency (K B value) of the test compound was determined from the degree of shift of the dose-response curve obtained by treatment with the test compound.
• the compounds of the present invention exhibited far more powerful antagonism to the trachea M 3 receptor than to the right atrium M 2 receptor. Therefore, the compounds of the present invention are more selective for trachea M 3 receptor.
• Bronchodilating action after administering each of the tested compound by inhalation was evaluated by measuring the inhibitory effect on airway resistance-increasing reaction in methacholine provocation test.
• 12 - 36 months old male beagle dogs (weighing 10 - 15 kg) were used, which were anesthetized with pentobarbital (30 mg/kg, i.v.) and intubated in their bronchus. After their respiration was stabilized, they were connected to Astograph (TCK-6100H, Chest Co.) and methacholine provocation test was conducted by 3Hz oscillation method.
• Methacholine which is an inhalation-inducing agent was diluted with physiologic salt solution to ten concentration levels starting from 40,000 ⁇ g/ml, successively as 20,000, 10,000, 5,000, 2,500, 1,250, 625, 312.5, 156 and 78 ⁇ g/ml.
• the test animals were made to inhale the methacholine solutions starting from that of the lowest concentration, each for one minute per solution, and changes in their respiration resistance was continuously recorded.
• the concentration level at which the respiration resistance reached twice the initial value was recorded as the methacholine reaction threshold value.
• methacholine reaction threshold values 1) of the dogs not treated with any of the tested medicines were measured at least twice at a week or longer interval(s) to select the dogs which showed reproducible reactions.
• bronchodilator activity of the test compound was determined according to the following equation. The result was shown in Table 3. Bronchodilation Action in Dogs Shift Value 5 minutes after 4 hours after 24 hours after Compound of Example 6 >30 >30 5.8 Compound of Example 54 >30 >30 3.9
• the compounds of formula [I] of the present invention exhibit potent and selective antagonism to muscarinic M 3 receptors and exhibit excellent pharmacological activity and long duration of action also when administered by inhalation.
• they can be administered to patients orally or parenterally, preferably by inhalation, as safe pharmaceutics exhibiting little side effects, in the treatment of, in particular, such respiratory diseases as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, chronic airway obstruction, fibroid lung, pulmonary emphysema and rhinitis.
• the compounds of the present invention for the treatment or prophylaxis of such diseases, they may be combined with pharmaceutically acceptable adjuvants in the usual manner to formulate pharmaceutical preparation forms suitable for administration.
• adjuvants various additives conventionally used in the field of pharmaceutics can be used.
• liquid preparations such as syrups, elixirs and injections
• solid preparations such as tablets, capsules, granules, powders and suppositories
• liquid preparations such as syrups, elixirs and injections
• These preparations may be formulated according to conventional techniques in the field of pharmaceutics.
• Liquid preparations may be in a form which is dissolved or suspended in water or other suitable medium prior to use.
• injections may be in the form advancedly dissolved or suspended in physiological saline solution or a glucose solution, or in powder form for reconstitution by dissolution or suspension in physiological saline or a glucose solution prior to use. If desired, such injections may contain buffer agents and/or preservatives.
• preparations for non-oral administration such as inhalant, they may be formulated into aerosol, inhaling powder or inhaling liquid.
• the inhaling liquid can take a form to be used as dissolved or suspended in water or other suitable medium at the application time.
• a compound of the present invention may be present at a ratio of from 1.0 to 100% by weight, preferably 1.0 to 60% by weight, based on the total weight of the preparation.
• These pharmaceutical preparations may additionally contain other therapeutically effective compounds.
• the dosage level and dosage schedule may vary according to sex, age and body weight of individual patient, severity of symptoms, type and range of the desired therapeutic effect, and the like.
• oral administration they can be administered in a daily dose of 0.1 to 100 mg/kg for an adult at one time or in several divided doses.
• parenteral administration they can be administered in a daily dose of 0.001 to 10 mg/kg for an adult, at one time or in several divided doses.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)-ethanoate.
• the product was obtained as a colorless, oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)-ethanoate.
• the product was obtained as a colorless, oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)-ethanoate.
• the product was obtained as a colorless, oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(1,3-benzodioxol-5-yl) ethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-ylmethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)-ethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using piperidin-4-ylmethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)-ethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using 3-endo-8-azabicyclo[3.2.1]-oct-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using 3-endo-8-azabicyclo[3.2.1]-oct-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3R)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)-ethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3R)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3R)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3R)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3S)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3S)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using (3S)-pyrrolidin-3-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using 1,2,3,6-tetrahydropyridin-4-ylmethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the treating procedures similar to the method of Example 1, using 2-(1,2,3,6-tetrahydropyridin-4-yl)ethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using 3-exo-8-azabicyclo[3.2.1]oct-3-ylmethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the procedures similar to the method of Example 1, using 2-((3R)-pyrrolidin-3-yl)ethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using 2-((3S)-pyrrolidin-3-yl)ethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using (3aR,6aS)-octahydrocyclopenta(c)pyrrol-5-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the procedures similar to the method of Example 1, using 2,4-cis-2-vinylpiperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using 3-aminopropyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using 1,3-trans-3-aminocyclobutyl (2R)-2-((1R)-3,3- difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless solid.
• the title compound was prepared by the procedures similar to the method of Example 1, using 1,3-cis-3-aminocyclobutyl (2R)-2-((1R)-3,3- difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using (1S,4S)-4-amino-2-cyclopentenyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the title compound was prepared by the procedures similar to the method of Example 1, using (1S,3S)-3-aminocyclopentyl (2R)-2-((1R)-3,3- difluorocyclopentyl)-2-hydroxy-2-phenylethanoate.
• the product was obtained as a colorless oily substance.
• the reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was dissolved in 1 ml of methanol. To the solution 10 mg of sodium borohydride was added, stirred for 10 minutes and acetone was added. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
• the product was dissolved in 2 ml of tetrahydrofuran, and to the solution 0.16 ml of 1.0M tetrahydrofuran solution of tetrabutylammonium fluoride was added, followed by an hour's standing at room temperature.
• the reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distililng the solvent off under reduced pressure, 51 mg of the title compound was obtained.
• Example 2 The compound of Example 1, 0.1 g, was dissolved in 900 ml of isotonic sodium chloride solution. Further isotonic sodium chloride solution was added to make the total amount 1000 ml, and the solution was given a sterile filtration through a membrane filter of 0.25 ⁇ m in pore size. One (1) ml each of the solution was poured in sterilized ampoules to provide a liquid inhalant.
• Example 1 Ten (10) g of the compound of Example 1 was homogeneously mixed with 70 g of lactose, and 100 mg of the mixed powder was filled in an exclusive powder inhaler, to provide a powder inhalant (400 ⁇ g per inhalation).
• those compounds of the present invention exhibit selective antagonism to muscarine M 3 receptors, they have little side effect and are safe. They exhibit excellent pharmacological effect and prolonged action also in inhalation therapy, and hence are useful as treating agents for diseases of respiratory organs.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pulmonology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=18706835

Family Applications (1)

Country Status (5)

Cited By (25)

Families Citing this family (16)

Citations (4)

Family Cites Families (10)

• 2001
  • 2001-07-10 WO PCT/JP2001/005987 patent/WO2002004402A1/ja active IP Right Grant
  • 2001-07-10 US US10/332,617 patent/US6846835B2/en not_active Expired - Fee Related
  • 2001-07-10 CA CA002415468A patent/CA2415468A1/en not_active Abandoned
  • 2001-07-10 AU AU2001271027A patent/AU2001271027B2/en not_active Ceased
  • 2001-07-10 EP EP01949925A patent/EP1302458A4/de not_active Withdrawn
• 2004
  • 2004-11-09 US US10/983,613 patent/US7192969B2/en not_active Expired - Fee Related
• 2007
  • 2007-01-03 US US11/648,614 patent/US7504432B2/en not_active Expired - Fee Related

Patent Citations (4)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events